During the previous two decades it has become apparent that genomic rearrangements are often the type of mutation that underlies neurological disease. This is so not only for neurodevelopmental disorders such as intellectual disability (ID) and different recognizable patterns of human malformation (e.g. Potocki- Lupski syndrome), but also for late-onset adult neurological disorders such as Charcot-Marie-Tooth disease. Moreover, genomic rearrangement can often underlie complex traits and sporadic diseases such as Parkinson, Alzheimer disease and other neurodegenerative processes. Contrary to prior interpretations, experimental evaluation of disease associated genomic rearrangements has often documented that they can be much more complex than anticipated. Complexities can occur at individual loci and give specific patterns for complex genomic rearrangements (CGR) such as duplication - normal - duplication (DUP-NML-DUP), or a triplication embedded within duplications (DUP-TRP-DUP). Furthermore, complexities can occur on a genomic level leading to complex chromosomal rearrangements and the phenomena of chromothripsis observed both in cancer and neurodevelopmental disorders, as well as an unusual pattern of multiple de novo copy number variants (CNVs) spread apparently randomly throughout the genome. The elucidation of mechanisms that can generate such complexities is a field that is truly in its infancy. We propose to further characterize complex genomic rearrangements (CGR) that have been found in association with neurological disease. Specifically, we will investigate and attempt to elucidate mechanisms for: 1) A CGR that consists of a triplicated segment in inverse orientation embedded within a duplicated segment of the genome (DUP-TRP/INV-DUP); a newly observed type of CGR with a proposed mechanism elucidated in our previous application; 2) The mechanism for recurrent triplications; 3) Elucidate the underlying molecular characteristics and breakpoint junctions of CGR that are accompanied by long genomic stretches of absence of heterozygosity (AOH), and resulting in both genomic (CGR) and genetic (AOH) alterations, and 4) We will attempt to isolate a gene important to the phenomena of multiple de novo CNV seemingly randomly distributed throughout the genome. The experimental approaches to be utilized to accomplish each one of these specific aims are now within our reach. It predominately requires genomic approaches that enable genomewide assays of variation such as array comparative genomic hybridization, genomewide SNP chips, exome sequencing, whole genome sequencing, and other mapping and molecular approaches for the delineation of specific breakpoint junctions. It is anticipated that completion of these ais will characterize these novel types of rearrangements and lend further insight into basic molecular mutational mechanisms that can cause myriad of neurological diseases.